Abstract 12086: Gamma Protein Kinase C Mediates Remote Incision-induced Cardioprotection
Remote cardioprotection via an abdominal incision is dependent on a neuronal-mediated pathway. However, translating incision-induced cardioprotection to treatment for humans is limited. Both ε protein kinase C (εPKC) and γPKC mediate pain nociception, with γPKC highly expressed only in nervous tissue. Thus, we determined whether selective pharmacological modulators of εPKC or γPKC given locally to the abdomen mimic or inhibit the protection afforded by an abdominal incision and the timing involved. Male rats (n=6/group) were acutely anesthetized, instrumented to measure hemodynamics, and a suture placed around the left anterior descending coronary artery (LAD). Rats were divided into groups and after surgical stabilization, underwent 30 minutes LAD occlusion and 2 hours reperfusion with infarct size measured. All agents were delivered only locally to the abdominal dermal layer. The selective PKC peptides were conjugated to TAT47-57 for intracellular delivery. For some groups, an abdominal incision was performed prior to ischemia, while in other groups either bradykinin (60ng/kg) or the εPKC selective activator, ψεRACK (1mg/kg), were given. In group subsets, either TAT47-57 (1mg/kg), or specific inhibitors of εPKC (εV1-2, 1mg/kg) or γPKC (γV5-3, 1mg/kg) were administered 10 minutes prior to these interventions. Treatment with the γPKC activator (ψcRACK, 1mg/kg), ψεRACK, or abdominal incision was also tested during ischemia. No changes in hemodynamics were noted. Abdominal incision, bradykinin or ψεRACK administration prior to myocardial ischemia-reperfusion reduced infarct size (43±2*%, 45±1*%, 44±2*% versus control: 63±2%, respectively, *P<0.001). Inhibition of either εPKC or γPKC completely blocked protection. Importantly, an abdominal incision or treatment with activators of either εPKC or γPKC during myocardial ischemia also reduced infarct size (45±2*%, 47±1*%, 45±1*%, respectively). Therefore, we identified pharmacological mimetics of remote abdominal incision-induced cardioprotection, including an activator of γPKC. These data also indicate that the cardioprotective and pain pathways are linked and suggest a novel role for γPKC in triggering remote cardioprotection.
- © 2012 by American Heart Association, Inc.